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The Role of Rituximab in the Treatment of Myasthenia Gravis

European Neurological Review, 2010;5(2):95-100 DOI:


Rituximab, a chimaeric monoclonal antibody against CD20, depletes B cells. It was initially approved for the treatment of B-cell lymphomas, but more recently has been approved for use in rheumatoid arthritis. It has been used extensively ‘off-label’ for the treatment of other autoimmune diseases with some evidence of efficacy, but there remain some as yet unanswered concerns about safety. Myasthenia gravis is the paradigm of an antibody-mediated disorder, and B cells are believed to play a crucial role. This article reviews experience of the efficacy and safety of rituximab in myasthenia gravis and considers predictive factors for the success and failure of rituximab in this disease.
Keywords: Rituximab, myasthenia gravis, antiacetylcholine receptor (anti-AChR), antimuscle-specific tyrosine kinase (anti-MuSK), predictive factors, clinical response
Disclosure: The authors have no conflicts of interest to declare.
Received: September 20, 2010 Accepted: November 08, 2010
Correspondence: Olivier Benveniste, Service de Médecine Interne 1, Groupe Hospitalier Pitié-Salpêtrière, 47-83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E:

Myasthenia gravis (MG) is an autoimmune disease associated with circulating antibodies, either against the nicotinic acetylcholine receptor (anti-AChR; ~80% of patients with generalised MG) or muscle-specific tyrosine kinase (anti-MuSK, 10% of patients),1 that induce a dysfunction of neuromuscular transmission owing to loss of functional receptors. Less commonly, MG remains confined to the ocular muscles. Only about 50% of such patients have antibodies detectable by standard assay (almost invariably anti-AChR) and most respond well to moderate doses of steroids without the need for more aggressive immunosuppression. In addition to anticholinesterase drugs, most patients with generalised MG require long-term treatment with steroids and immunosuppressive drugs, of which the most commonly used include azathioprine, mycophenolate mofetil and ciclosporin.2–5 Between 5 and 10% of patients remain refractory to such treatment.2,6 Other immunosuppressive drugs may then be considered, including cyclophosphamide,7 tacrolimus8 and etanercept,9 whose efficiency has not been assessed on the basis of double-blind clinical trials. Intravenous immunoglobulins (IVIg)10 and plasma exchange11 are used for acute exacerbations while waiting for other treatments to become effective, but have no sustained beneficial effect. Newer effective molecules with a good safety profile are undoubtedly needed.

Rituximab (RTX), a chimaeric monoclonal antibody specific for human CD20 that targets B lymphocytes, was first developed (and licensed) for the treatment of B-cell lymphoma12,13 and is used at a dose of 375mg/m2/body surface area once weekly for four weeks. It was noted that in patients with lymphoma treated with RTX and concomitantly suffering from autoimmune diseases (rheumatoid arthritis [RA]14 or MG15) the autoimmune diseases were ameliorated. Subsequent to these early reports, RTX has been used in many autoimmune diseases where B cells seem to play a role, not only in RA. These pivotal studies16,17 led to the molecule being licensed in cases of RA resistant to antitumour necrosis factor (anti-TNF) first-line therapy (RTX 1g on days one and 15), and also being used (off-label) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis,18,19 multiple sclerosis,20,21 systemic lupus erythematosus (SLE),22 immune thrombocytopenic purpura (ITP)23 and pemphigus.24

  1. Farrugia ME, Vincent A, Curr Opin Neurol, 2010;23(5):489–95.
  2. Tindall RS, et al., N Engl J Med, 1987;316:719–24.
  3. Saperstein DS, Barohn RJ, Sem Neurol, 2004;24:41–75.
  4. Palace J, et al., Neurology, 1998;50:1778–83.
  5. Meriggioli MN, et al., Neurology, 2003;61:1438–40.
  6. Ciafaloni E, et al., Neurology, 2000;55:448–50.
  7. Drachman DB, et al., Ann Neurol, 2003;53:29–34.
  8. Ponseti JM, et al., Neurology, 2005;64:1641–3.
  9. Rowin J, et al., Neurology, 2004;63:2390–92.
  10. Gajdos P, et al., Cochrane Database Syst Rev, 2003:CD002277.
  11. Newsom-Davis J, et al., N Engl J Med, 1978;298:456–7.
  12. Maloney DG, et al., J Clin Oncol, 1997;15:3266–74.
  13. McLaughlin P, et al., J Clin Oncol, 1998;16:2825–33.
  14. Protheroe A, et al., Rheumatology (Oxford), 1999;38:1150–2.
  15. Gajra A, et al., Am J Hematol, 2004;77:196–7.
  16. Edwards JC, et al., N Engl J Med, 2004;350:2572–81.
  17. Cohen SB, et al., Arthritis Rheum, 2006;54:2793–2806.
  18. Stone JH, et al., N Engl J Med, 2010;363:221–2.
  19. Jones RB, et al., N Engl J Med, 2010;363:211–20.
  20. Bar-Or A, et al., Ann Neurol, 2008;63:395–400.
  21. Hauser SL, et al., N Engl J Med, 2008;358:676–88.
  22. Terrier B, et al., Arthritis Rheum, 2010;62:2458–66.
  23. Godeau B, et al., Blood, 2008;112:999–1004.
  24. Joly P, et al., N Engl J Med, 2007;357:545–52.
  25. Zaja F, et al., Neurology, 2000;55:1062–3.
  26. Wylam ME, et al., J Pediatr, 2003;143:674–7.
  27. Hain B, et al., Muscle Nerve, 2006;33:575–80.
  28. Baek WS, et al., J Neurol Neurosurg Psychiatry, 2007;78:771.
  29. Thakre M, et al., J Neurol, 2007;254:968–9.
  30. Diaz-Manera J, et al., Nat Clin Pract Neurol, 2007;3:405–10.
  31. Evoli A, et al., Ann N Y Acad Sci, 2008;1132:76–83.
  32. Tran H, et al., Nat Clin Pract Oncol, 2008;5:234–8.
  33. Kerkeni S, et al., Muscle Nerve, 2008;38:1343–5.
  34. Strober J, et al., Arch Neurol, 2009;66:659–61.
  35. Tzaribachev N, et al., Cases J, 2009;2:6609.
  36. Sadnicka A, et al., Rituximab in the treatment of three coexistent neurological autoimmune diseases: chronic inflammatory demyelinating polyradiculoneuropathy, Morvan syndrome and myasthenia gravis, J Neurol Neurosurg Psychiatry, 2010; [Epub ahead of print].
  37. Masroujeh R, et al., Int J Hematol, 2010;91:522–4.
  38. Illa I, et al., J Neuroimmunol, 2008;201–202:90–94.
  39. Lebrun C, et al., Eur J Neurol, 2009;16:246–50.
  40. Nelson RP, Jr, et al., J Clin Neuromuscul Dis, 2009;10: 170–77.
  41. Stieglbauer K, et al., J Neurol Sci, 2009;280:120–22.
  42. Butterly SJ, et al., Intern Med J, 2010;40:443–52.
  43. Lindberg C, Bokarewa M, Rituximab for severe myasthenia gravis – experience from five patients, Acta Neurol Scand, 2010; [Epub ahead o f print].
  44. Zebardast N, et al., Muscle Nerve, 2010;41:375–8.
  45. Maddison P, et al., The use of rituximab in myasthenia gravis and Lambert-Eaton myasthenic syndrome, J Neurol Neurosurg Psychiatry, 2010; [Epub ahead of print].
  46. Clynes RA, et al., Nat Med, 2000;6:443–6.
  47. Reff ME, et al., Blood, 1994;83:435–45.
  48. Leandro MJ, et al., Arthritis Rheum, 2006;54:613–20.
  49. Roll P, et al., Arthritis Rheum, 2008;58:1566–75.
  50. Lindstrom JM, et al., Neurology, 1976;26:1054–9.
  51. Vincent A, Nat Rev Immunol, 2002;2:797–804.
  52. Ragheb S, et al., Autoimmunity, 1999;31:55–66.
  53. Vincent A, et al., Lancet, 2001;357:2122–8.
  54. Murai H, et al., J Neuroimmunol, 1997;76:61–9.
  55. Onodera J, et al., Ann Neurol, 1996;39:521–8.
  56. Ragheb S, et al., Arch Neurol, 2008;65:1358–62.
  57. Martin F, Chan AC, Annu Rev Immunol, 2006;24:467–6.
  58. Popa C, et al., Rheumatology (Oxford), 2007;46:626–30.
  59. Keystone E, et al., Arthritis Rheum, 2007;56:3896–3908.
  60. Benucci M, et al., Autoimmun Rev, 2010;9(12):801–3.
  61. Melms A, et al., J Clin Invest, 1988;81:902–8.
  62. Manfredi AA, et al., J Clin Invest, 1993;92:1055–67.
  63. Danke NA, et al., J Immunol, 2004;172:5967–72.
  64. Riley JL, et al., Immunity, 2009;30:656–65.
  65. Luther C, et al., J Immunol, 2009;183:841–8.
  66. Balandina A, et al., Blood, 2005;105:735–41.
  67. Sfikakis PP, et al., Clin Immunol, 2007;123:66–73.
  68. Stasi R, et al., Blood, 2008;112:1147–50.
  69. Hultin LE, et al., Cytometry, 1993;14:196–204.
  70. Cartron G, et al., Blood, 2002;99:754–8.
  71. Anolik JH, et al., Arthritis Rheum, 2003;48:455–9.
  72. Pers JO, et al., Arthritis Rheum, 2007;56:1464–77.
  73. Dass S, et al., Arthritis Rheum, 2008;58:2993–9.
  74. Schroder C, et al., Transpl Immunol, 2003;12:19–28.
  75. Moller B, et al., Arthritis Res Ther, 2009;11:R62.
  76. Quartuccio L, et al., Rheumatology (Oxford), 2009;48: 1557–9.
  77. Farrugia ME, et al., Brain, 2006;129:1481–92.
  78. Albert D, et al., Ann Rheum Dis, 2008;67:1724–31.
  79. Todd DJ, Helfgott SM, J Rheumatol, 2007;34:430–33.
  80. Carson KR, et al., Blood, 2009;113:4834–40.
  81. D’Souza A, et al., Clin Lymphoma Myeloma Leuk, 2010;10(1):E1–9.
  82. Paues J, Vrethem M, J Clin Virol, 2010;48:291–3.
  83. Tsutsumi Y, et al., Expert Opin Drug Saf, 2005;4:599–608.
  84. Jaretzki A, et al., Neurology, 2000;55:16–23.
Keywords: Rituximab, myasthenia gravis, antiacetylcholine receptor (anti-AChR), antimuscle-specific tyrosine kinase (anti-MuSK), predictive factors, clinical response